title: High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase.
abstract: Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 weeks. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice.
  
  
  CONCLUSIONS
  An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO.
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.forename: David J
authors.initials: DJ
authors.lastname: Orlicky
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.forename: Rachel H
authors.initials: RH
authors.lastname: McMahan
authors.forename: Manal F
authors.initials: MF
authors.lastname: Abdelmalek
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Rosen
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jackman
authors.forename: Paul S
authors.initials: PS
authors.lastname: MacLean
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.forename: Aruna
authors.initials: A
authors.lastname: Asipu
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Inaba
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosugi
authors.forename: Waichi
authors.initials: W
authors.lastname: Sato
authors.forename: Shoichi
authors.initials: S
authors.lastname: Maruyama
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sánchez-Lozada
authors.forename: Yuri Y
authors.initials: YY
authors.lastname: Sautin
authors.forename: James O
authors.initials: JO
authors.lastname: Hill
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D002149:Energy Intake; D005234:Fatty Liver / Q000209:etiology*; D005631:Fructokinases / Q000502:physiology*; D005632:Fructose / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013395:Sucrose / Q000008:administration & dosage*; D015430:Weight Gain
chemical_list: D005632:Fructose; D013395:Sucrose; D005631:Fructokinases; C046173:fructokinase